RESUMEN
Inhibition of mPGES-1, the terminal enzyme in the arachidonic acid/COX pathway to regulate the production of pro-inflammatory prostaglandin PGE2, is considered an attractive new therapeutic target for safe and effective anti-inflammatory drugs. The discovery of a novel series of orally active, selective benzoxazole piperidinecarboxamides as mPGES-1 inhibitors is described. Structure-activity optimization of lead 5 with cyclohexyl carbinols resulted in compound 12, which showed excellent in vitro potency and selectivity against COX-2, and reasonable pharmacokinetic properties. Further SAR studies of the benzoxazole ring substituents lead to a novel series of highly potent compounds with improved PK profile, including 23, 26, and 29, which were effective in a carrageenan-stimulated guinea pig air pouch model of inflammation. Based on its excellent in vitro and in vivo pharmacological, pharmacokinetic and safety profile and ease of synthesis, compound 26 (PF-4693627) was advanced to clinical studies.
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inflamación/tratamiento farmacológico , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Descubrimiento de Drogas , Humanos , Inflamación/enzimología , Oxidorreductasas Intramoleculares/metabolismo , Prostaglandina-E Sintasas , Relación Estructura-ActividadRESUMEN
Microsomal prostaglandin E(2) synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. In the preceding letter, we detailed the discovery of clinical candidate PF-04693627, a potent mPGES-1 inhibitor possessing a novel benzoxazole structure. While PF-04693627 was undergoing further preclinical profiling, we sought to identify a back-up mPGES-1 inhibitor that differentiated itself from PF-04693627. The design, synthesis, mPGES-1 activity and in vivo PK of a novel set of substituted benzoxazoles are described herein. Also described is a conformation-based hypothesis for mPGES-1 activity based on the preferred conformation of the cyclohexane ring within this class of inhibitors.
Asunto(s)
Benzoxazoles/química , Benzoxazoles/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Benzoxazoles/síntesis química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Humanos , Oxidorreductasas Intramoleculares/química , Oxidorreductasas Intramoleculares/metabolismo , Modelos Moleculares , Conformación Molecular , Prostaglandina-E Sintasas , Relación Estructura-ActividadRESUMEN
A series of acidic triazoles with activity as soluble guanylate cyclase stimulators is described. Incorporation of the CF(3) triazole improved the overall physicochemical and drug-like properties of the molecule and is exemplified by compound 25.
Asunto(s)
Ácidos/química , Activadores de Enzimas/farmacología , Guanilato Ciclasa/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Triazoles/farmacología , Guanilil Ciclasa Soluble , Triazoles/químicaRESUMEN
A series of C-2 pyrroloquinoline analogs designed to improve aqueous solubility were examined for herpesvirus polymerase and antiviral activity. Several analogs were identified that maintained the antiviral activity of the previous development candidate against HCMV, HSV-1 and VZV, but with significantly improved aqueous solubility.
Asunto(s)
Antivirales/química , Herpesviridae/enzimología , Inhibidores de la Síntesis del Ácido Nucleico , Pirroles/química , Quinolinas/química , Antivirales/síntesis química , Antivirales/farmacología , Citomegalovirus/efectos de los fármacos , ADN Polimerasa Dirigida por ADN/metabolismo , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 3/efectos de los fármacos , Humanos , Pirroles/síntesis química , Pirroles/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Solubilidad , Relación Estructura-ActividadRESUMEN
The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.
Asunto(s)
Diseño de Fármacos , Agonismo Inverso de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Piridinas/administración & dosificación , Piridinas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Piridinas/farmacocinética , Células Th17/efectos de los fármacos , Células Th17/metabolismoRESUMEN
Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Ciclobutanos/farmacología , Janus Quinasa 1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Sulfonamidas/farmacología , Animales , Artritis Experimental/tratamiento farmacológico , Ciclobutanos/química , Ciclobutanos/farmacocinética , Ciclobutanos/uso terapéutico , Perros , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Janus Quinasa 1/química , Janus Quinasa 2/antagonistas & inhibidores , Modelos Moleculares , Conformación Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Pirroles/química , Pirroles/farmacocinética , Pirroles/uso terapéutico , Ratas , Especificidad por Sustrato , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéutico , Distribución TisularRESUMEN
We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.